Single-soma transcriptomics of tangle-bearing neurons in Alzheimer’s disease reveals the signatures of tau-associated synaptic dysfunction

Abstract

Aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is closely associated with neuronal death and cognitive decline in Alzheimer's disease (AD). To define the signatures that distinguish between aggregation-prone and resistant cell states in AD, we developed a FACS-based method for the high-throughput isolation and transcriptome profiling of individual cells with cytoplasmic aggregates and profiled 63,110 somas from human AD brains. By comparing NFTbearing and NFT-free somas within and across neuronal subtypes, we identified the cell-type-specific and shared states. NFT-bearing neurons shared a marked upregulation of genes associated with synaptic transmission, including a core set of 63 genes enriched for synaptic vesicle cycle and transsynaptic signaling, whereas glucose metabolism and oxidative phosphorylation changes were highly neuronal-subtype-specific. Apoptosis was modestly enriched in NFT-bearing neurons despite the strong link between tau and cell death. Our datasets provide a resource for investigating taumediated neurodegeneration and a platform for biomarker and drug target discovery.

Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer’s disease

“…Our finding that increased CSF t-tau was associated with increased levels of neuronal plasticity proteins provides further support for the role of tau in neuronal plasticity ( 21,23 ). Tau may influence gene expression itself ( 21-23 ), which may explain why knock-out of tau in AD mice models prevented hyperactivation ( 32,33 ).…”

“…SUZ12 and REST were previously associated with increased expression of plasticity genes in iPSC neuronal progenitor cells of sporadic AD individuals, of which 63 proteins were also increased in CSF in our study in individuals with abnormal Aβ 1-42 and t-tau ( 15 ). REST has also been associated with the increased expression of plasticity related genes in tangle bearing neurons ( 21 ). Tau may increase gene expression directly or indirectly by increasing H3K9 acetylation, REST translocation or chromatin relaxation ( 15,22,23 ).…”

Spatially resolved transcriptomics reveals unique gene signatures associated with human temporal cortical architecture and Alzheimer’s pathology

“…We compared the gene expression between AD and control samples, and found 2,164 genes were significantly upregulated while 89 were downregulated in AD samples (Supplementary Table 4). Interestingly, some DEGs have also been identified in recently published bulk RNA-Seq 28 , snRNA-Seq 9, 10, 12 , single-soma RNA-Seq 29 , single microglia RNA-Seq 30 and the proteomic datasets 31 from human AD and control cases (Figure 4a). Furthermore, the GO enrichment analysis of these upregulated DEGs reveals many known AD-related biological processes including protein targeting to membrane and ER, RNA catabolic process, viral gene expression, synaptic transmission and trans-synaptic signaling, protein folding and gliogenesis (Fig.…”

“…7). This gene encodes the 14-3-3 protein, which is recently found to be increased in tangle-bearing neurons and may be involved in the neurodegeneration induced by tau aggregation 29 . It should be noted that 14-3-3 proteins (YWHAH, YWHAB, YWHAQ, and YWHAZ) have been found in NFTs 61 , and the latter three of them stimulate the phosphorylation of tau and the formation of NFTs 62 .…”

Whole-Cell Dissociated Suspension Analysis in Human Brain Neurodegenerative Disease: A Pilot Study

“…However, this technology is limited by the considerable time and personnel investment as well as the limited ability to mark target cells phenotypically prior to microdissection. In recent years, methods have been developed that allow an initial creation of single-cell suspensions (Darmanis et al, 2015; Guez-Barber et al, 2012; Otero-Garcia et al, 2020) or single nuclei isolation from solid fixed, fresh or frozen tissue (Bakken et al, 2018; Blue B. Lake et al, 2016; B.…”